SK112094A3 - Method of vitamin d producing - Google Patents

Abstract

PCT No. PCT/EP93/00498 Sec. 371 Date Sep. 9, 1994 Sec. 102(e) Date Sep. 9, 1994 PCT Filed Mar. 5, 1993 PCT Pub. No. WO93/19057 PCT Pub. Date Sep. 30, 1993.A process for preparing dl- alpha -tocopherol or dl- alpha -tocopheryl acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytol or isophytol in a solvent at elevated temperature, with or without subsequent esterification of the resulting tocopherol with acetic anhydride, entails the reaction being carried out in the presence of a mixture of ortho-boric acid and certain aliphatic di- or tricarboxylic acids, preferably in the presence of a mixture of ortho-boric acid and oxalic acid.

Description

Technical field

The present invention relates to an improved process for the production of vitamin E by acid catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytol.

BACKGROUND OF THE INVENTION

It is known that d, l-α-tocopherol (vitamin E) is produced by a reaction

2,3,5-trimethylhydroquinone and phytol or isophytol (IP) at elevated temperature in a low-polar solvent in the presence of various acid catalysts.

According to the data contained in Chem. Abstracts (C.A.) 84, 59792 (1976) and Chem. Abstracts 85, 46898 (1976), the reaction may be carried out in the presence of silica and / or alumina with acids.

According to Chem. 73, 77483 (1970), Chem. 80, 3385 (1974), Chem. 80, 3386 (1974), Chem. Abstracts 73, 98799 (1970) and DE-OS 22 08 795, the reaction can also be carried out in the presence of zinc chloride in combination with acids such as hydrohalic acids, in particular hydrochloric or trichloroacetic acid or acetic acid.

According to DE-A 22 08 795, it is also possible to use zinc chloride in a mixture with sodium hydrogen sulphate, sulfuric acid or p-toluenesulphonic acid, in a molar ratio of from 1: 3 to 1: 1.

According to the information contained in Chem. Abstracts 84, 74471 (1976), can be carried out in perchlorethylene, in the presence of a 87:13 silica / alumina mixture as a catalyst.

According to U.S. Pat. No. 3,459,773, vitamin E is obtained by reacting phytol or isophytol with 2,3,5-trimethylhydroquinone in an inert solvent using a macroreticular cation exchange resin of the sulfonic acid type.

A common feature of these known processes is that they do not permit the production of vitamin E on a large scale in the required purity.

To overcome this problem, a reaction according to DE 27 43 920 was carried out in the presence of a mixture of silicic acid and / or alumina or silica gel and zinc chloride, as well as a strong acid such as concentrated hydrochloric acid, sulfuric acid, phosphoric acid or p-toluenesulfonic acid.

The disadvantage of this method, as with the above-mentioned methods, is that corrosion problems arise and that zinc ion loads can occur in the waste water.

The object of the invention is to find a catalyst system for the reaction

2,3,5-trimethylhydroquinone with phytol or isophytol to vitamin E, which would make it easier to produce vitamin E also on a larger scale than in the prior art. To this end, the catalytic system must be non-toxic (such as boron trifluoride adducts), have no corrosive effects (such as zinc chloride, hydrochloric acid, formic acid and phosphoric acid), so that unwanted side reactions such as dehydration of isophytol to phytadiene are suppressed and that the reactions of expensive and sensitive starting materials are catalyzed also when equimolar amounts are used in high yields, since excess starting materials are separable only with a large consumption of the reaction product.

SUMMARY OF THE INVENTION

It has recently been found that a mixture of orthoboric acid on the one hand and certain dicarboxylic acids, such as oxalic acid or tartaric acid or tricarboxylic acids, such as citric acid, on the other hand, in particular a mixture of orthoboric acid and oxalic acid, best meets the above requirements. Each component alone catalyses the reaction insufficiently. The almost unexpected synergistic effect allows an optimal result.

The object of the present invention is a correspondingly improved process for the preparation of d, la-tocopherol or d, d-α-tocopheryl acetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone with phytol or isophylene in a solvent at elevated temperature and optionally followed by esterification of the tocopherol obtained acetic acid, characterized in that the reaction is carried out in the presence of a mixture of orthoboric acid, on the one hand, and oxalic acid, tartaric acid or citric acid, on the other hand.

The preparation of 2,3,5-trimethylhydroquinone and phytol or isophytol is known and therefore does not need to be described in detail.

The process is particularly advantageous when oxalic acid or tartaric acid, in particular oxalic acid, is used as a catalyst in admixture with orthoboric acid.

The condensation of 2,3,5-trimethylhydroquinone with phytol or isophytol according to the invention is carried out in the presence of from about 0.2 to 7 mol%, preferably from 0.5 to 5 mol%, of orthoboric acid and from 0.4 to 14 mol%. preferably from 0 to 10 mol% of oxalic acid, tartaric acid or citric acid per mole of 2,3,5-trimethylhydroquinone. The orthoboric acid and carboxylic acid are preferably used in a molar ratio of about 1:12.

Alkyl aromatic compounds, such as toluene or xylene or ketones, with a boiling point of about 70 to 140 ° C are preferably used as solvents for the reaction. Particular preference is given to working in aliphatic ketones, such as diethyl ketone or methyl isopropyl ketone. However, highly boiling solvents such as tetraline are particularly suitable when condensation is carried out under strongly reduced pressure.

Reaction temperatures are generally from about 70 to 130 ° C, preferably from 90 to 110 ° C.

In order to carry out the reaction, it is generally carried out by adding a solution of 2,3,5-trimethylhydroquinone and a catalyst mixture in a solvent, drying the reaction mixture with water and cooling while cooling. Upon completion by an effective liquid: in a manner known per se, the ketone after the reaction must be replaced with a water-immiscible solvent, a hydrocarbon, so that the crude obtained can be washed using alkylaromatic compounds before solvent exchange can be dispensed with. However, using the recycle circuit to remove phytol or isophytol under reaction (as determined by high chromatography), the reaction mixture is worked up using ketones as solvent, and in particular tocopherol is removed. solvents of alkylaromatic compounds as solvents has the disadvantage that the catalyst sublimates from the reaction mixture in small amounts.

The washing of the crude tocopherol can be carried out e.g. dilute aqueous sodium hydroxide solution, a mixture of methanol and dilute aqueous hydrochloric acid, and finally a mixture of methanol and dilute aqueous sodium bicarbonate. The tocopherol thus obtained can either be isolated as such or converted to tocopheryl acetate by an acid-catalyzed reaction with an excess of acetic anhydride.

The tocopheryl acetate thus obtained can be purified by fractional distillation under strongly reduced pressure.

The process may be continuous.

Perform discontinuously, but also

With the process of the present invention, d, l-α-tocopherol or its acetate can be obtained in a simple and environmentally friendly manner in very good yield and purity.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a flask of 11 was charged 76 g (0.5 mol)

2,3,5-trimethylhydroquinone with 0.973 g (15.7 mmol) of orthoboric acid and 2.83 g (31.4 mmol) of oxalic acid in 200 g (245.2 ml) of diethyl ketone. The reaction mixture was contacted with 160 g (0.535 mol) of isophytol during drying via a water removal circuit for 3 hours.

After completion of the addition of isophytol, the reaction mixture was refluxed for 30 minutes and then allowed to cool. High-performance liquid chromatography (100% methanol, Zorbax ODS 5 μπι, 4 mm x 25 mm column, flow rate 1 ml / min, ultraviolet detector at 220 nm) determined that conversion to 2,3,5-triethylhydroquinone is greater than 96%.

Finally, from the solution obtained, dilute aqueous hydroxide solution

2,3,5-trimethylhydroquinone and the tocopherol catalyst are extracted with unreacted sodium and then the tocopherol solution is decolourised with an aqueous alkaline solution of sodium sulfite.

Thereafter, the diethyl ketone was distilled off under reduced pressure, and the remaining residue was contacted with 66 g (0.646 mol) of acetic anhydride and 1.5 ml of a solution of 1 ml of sulfuric acid in 100 ml of acetic anhydride and (while monitoring by high performance liquid chromatography). the reaction mixture is heated to reflux.

Finally, the acetic anhydride / acetic acid mixture is distilled off at 2 kPa and further distillation under reduced pressure yields 224 g of pure tocopheryl acetate. This corresponds to a yield of 91.7% of theory.

Examples 2-4

A mixture of 22.8 g (0.15 mmol) of 2,3,5-trimethylhydroquinone, 9.4 mmol of the carboxylic acid shown in the table and 0.293 g (4.7 mmol) of orthoboric acid in 70 ml of diethyl ketone is added dropwise, Contact with 48 g (0.16 mol) of isophytol, while removing water through the circulating circuit, for 90 minutes of vigorous refluxing. Finally, the reaction mixture is refluxed for 2 hours. Approximately 2 mL of water was removed by the circuit during the reaction.

Finally, the diethyl ketone is distilled off under reduced pressure (bath temperature 60 ° C, water pump, rotary evaporator), the residue is taken up in 100 ml of heptane and the heptane solution is washed twice with 150 ml of a 1: 1 mixture of methanol and 1N hydrochloric acid. then once with a mixture of 150 ml of methanol and 150 ml

Of a 2.5% aqueous solution of sodium bicarbonate and finally once with 75 ml of a 1: 1 mixture of methanol and water.

Evaporation of heptane under reduced pressure (bath temperature 70 ° C, water pump, rotary evaporator) gave crude tocopherol.

The crude tocopherol was acetylated with 19.2 g (0.19 mol) of acetic anhydride in the presence of a catalytic amount of sulfuric acid (at 142-145 ° C for 4 hours) and the reaction mixture was finally evaporated under reduced pressure. The crude tocopheryl acetate thus obtained is subjected to fractional distillation under strongly reduced pressure and the yield is determined by gas chromatography. The yields of d, Ι-α-tocopheryl acetate obtained are shown in the following table.

table

Example Carboxylic acid Yield on d, d-α-tocopheryl acetate (% of theory) oxalic acid L - (+) - tartaric citric acid

Example 5

(a) A mixture of 150 ml of toluene, 22.8 g (0.15 mol) is charged to a 500 ml mixing apparatus equipped with a thermometer, a dropping funnel and a circulating water separating device.

2,3,5-trimethylhydroquinone, 0.29 g (5 mmol) of orthoboric acid and 0.85 g (10 mmol) of oxalic acid. This mixture was contacted with 48 g (0.16 mol) of isophytol for 1 hour, under vigorous reflux (approximately 100 ° C at 65 kPa), and the water was removed via a circulating circuit, and the mixture was stirred for 1 hour. let it react for one hour. Approximately 2.4 ml of water are separated by a circuit.

Finally, the reaction mixture is cooled to room temperature and washed three times with 150 ml of a mixture of equal parts of methanol and 1 molar hydrochloric acid and then twice with 150 ml of 50% aqueous methanol each and finally evaporated on a rotary evaporator ( ).

19.2 g (0.19 mol) of acetic anhydride and a trace of sulfuric acid are then added to the obtained crude tocopherol. The mixture was refluxed for 4 hours and finally evaporated on a rotary evaporator (bath temperature 65 ° C at 3 kPa). The crude tocopheryl acetate thus obtained is subjected to fractional distillation under strongly reduced pressure. 65.2 g of .alpha.-tocopheryl acetate are obtained at a temperature of 200 DEG-210 DEG C. and a pressure of 1 Pa, which, according to GC analysis, has a purity of 98%. This corresponds to a yield of 90% of theory.

The yield obtained can be improved to a small extent by changing the treatment of the reaction mixture, provided that the processing variant b) described below is carried out.

b) The reaction mixture is worked up as described under a), but after the reaction and subsequent reaction with isophytol, toluene is distilled off (on a rotary evaporator at 65 ° C and 3 kPa) and the solvent is replaced with an equal amount of n-heptane. The reaction mixture is washed as described under a) and then n-heptane is distilled off under reduced pressure.

The α-tocopheryl acetate obtained by fractional distillation has a purity of 98% according to gas chromatography. Yield: 92%.

Example 6

A mixture of 150 ml of tetraline, 22.8 g of 2,3,5-trimethylhydroquinone, 0.29 g of orthoboric acid and 0.85 g of oxalic acid is introduced into a 500 ml mixing apparatus equipped with a thermometer and an addition funnel. This mixture is contacted with 48 g of isophytol for 1 hour, under vigorous reflux (approximately 95-100 ° C at 8 kPa), and then left to react for one hour. The reaction water is removed as a steam through a heated bridge during the reaction and condensed in a chilled flask (approximately 2.6 g of water is collected). A small proportion of the catalyst is also added.

Finally, the reaction mixture is cooled to 40 [deg.] C., 100 ml of heptane are added and the mixture is washed three times with 150 ml of a solution of equal parts of methanol and 1 molar aqueous hydrochloric acid and then twice with 100 ml of 50% aqueous methanol each. At this point, the organic phase is freed by rotary evaporation of heptane (bath temperature 65 ° C at 3 kPa) and the tetralin is distilled off over a bridge (at 50 ° C and about 50 Pa).

19.2 g of acetic anhydride and a trace of sulfuric acid are added to the residue. The resulting mixture was heated to reflux for 4 hours and then evaporated on a rotary evaporator (bath temperature 65 ° C at 3 kPa and finally 500 Pa). Distillation under high vacuum over a bridge at 204 to 210 ° C and 2 Pa gives 68.6 g of α-tocopheryl acetate, which is 92% pure by gas chromatography (GC) analysis. This corresponds to a yield of 89% of theory.

TV-to-fy

Claims (2)

PATENT CLAIMS Process for the preparation of d, 1a-tocopherol or d, 1-a-tocopheroacetate by acid-catalyzed reaction of 2,3,5-trimethylhydroquinone with a phytol or isophylol in a solvent at elevated temperature and optionally subsequent esterification of the obtained tocopherol with acetic anhydride, The method according to claim 1, wherein the reaction is carried out in the presence of a mixture of orthoboric acid, on the one hand, and oxalic acid, tartaric acid or citric acid, on the other hand. Process according to Claim 1, characterized in that the reaction is carried out in a mixture of orthoboric acid and oxalic acid. Process for the preparation of d, 1,1-α-tocopherol or d, l-α-tocopheryl acetate according to claim 1, characterized in that the reaction is carried out in a mixture of orthoboric acid and tartaric acid. Process for the preparation of d, 1-α-tocopherol or d, Ι-α-tocopheryl acetate according to claim 1, characterized in that the reaction is carried out in the presence of from 0.5 to 5 mol% of orthoboric acid and from 1 to 10%. molar oxalic acid, tartaric acid or citric acid per mol 2,3,5-trimethylhydroquinone.